11alpha, 17alpha-dihydroxy-normal pregnane-3, 20-dione and 11alpha-esters thereof



U ted St es Pa en 11bz,17oc-DIHYDROXY--: NORMAL PREGNANE-jo DIONE llw-ESTERS THEREOF v 2,877,241 Patented Mar. 10, 1959 yield 17a-hydroxy-21-acetoxyallopregnane-3,l1,20-trione, a steroid compound which was converted by Djerassi et a].

I [Nature, 168, 28 (1951)] to cortisone acetate Gunther S. Fonken, Kalamazoo, Robert H. Levin, Kala 4 Claims. (Cl. ace -397.45

The present invention relates to 1'1 a oxygenated steroids and is particularly concerned with novel ll-oxygenated- 17u-hydroxy-pregnane-3,ZO-diones selected from the group consisting of normal and allo 11a,l7u-dihydroxypregnane- 3,20-dione and normal and allo 11ot-acyloxy-17a-hydroxypregnane-3,20-dione, wherein the acyl radical is a hydrocarbon carboxylic acid containing up to and including eight carbon atoms.

This application is a continuation-in-part of copending application Serial Number 299,232, filed July 16, 1952, now Patent No. 2,714,599, issued August 2, 1955,

The novel normal and allo 11a,17a-dihydroxypregn'ane- 3,20-dionesare obtained by selective oxidation of normal and allo 30:,11e,17e-trihydroxypregnana20-one with tertiary butyl hypochlorite or by hydrogenation of 1100,1741- dihydroxyprogesterone in the presence of a palladium catalyst; thenovel l'l -esters, by oxidation of llct-a'cyl'oxy 3a,17u-dihydoxypregnan-20 one' (normal or allo) withtertiary butyl hypochlorite' or by hydrogenation of an 1 lm-acyloxy-l'Zu-hydroXyprogesterone wherein the acyl radical of a hydrocarbon carboxylic acid containing up to and including eight carbon atoms, in the presence of a p'alladium catalyst or by acylation of the 1la,17a-dihydroxypregnane-3,20-dio'nes. dione or Ila-esters thereof (unless otherwise specified these terms shall include both the normal and allo forms) can also be obtained by reducing 4-chloroor 4-bromo 11a,17a-dihydroxypregnane-3,ZO-diones or 11a.- esters thereof with zinc and acetic acid.

It is an object of the present invention to provide l1a,17u-dihydroxypregnane-3.ZO-dione (normal and allo) and' Ila-esters thereof. Other objects of the present invention will be apparent to those skilled in the art to which this invention pertains.

The novel compounds of the present invention, 11,17adihydroxypregnane-3,20-dione and esters thereofihave utility per se as physiologically active agents having gonadohormonal activity without inhibition of the gonadotrophic hormonal secretion. Both the normal and allo compound, i. e., l1a,17u-dihydroxynormalpregnane3,20- dione and lla,l7or'dihydroxyallopregnane-3,20-dioneare furthermore valuable as intermediates for the conversion into physiologically active adrenal hormones. For example, 11a,l7a-dihydroxynormalpregnane-3,20-dione can be converted to cortisone acetate, by forming the 3-ketal with ethylene glycol, brominating with bromine in acetic acid to obtain 110 17 a-dihydmXy-Zl-bromopregnane-3 ,20- dione 3-ethylene glycol ketal, hydrolyzing the 3-ketal group with hydrochloric acid to obtain 1la,17a-dihydroxy- 21-bromopregnane-3,ZO-dione, oxidizing this dione with chromic acid to obtain 17a-hydroxy-2l-bromopregnane 3,11,20-trione which can be converted to cortisone acetate by the method of Kritchevsky, Garmaise and Gallagher [1. Am. Chem. Soc., 74, 484 (1952)]. Similarly 11a,- 17a-dihydroxyallopregnane-3,20-dione is converted into 170: hydroxy-Z1-bromoallopregnane-3,11,20-trione 1 and the resulting trione reacted with potassium acetate'to 1 la,17a-dihydroxypregnane-3,20-

A starting compound for the preparation of 11,l7a-

dihydroxynormalpregnane-3,ZO-dione is 3u,11'a,17bt-trihy-,- 1 .drorrypregnan-ZO-one prepared from 3a,17a-dihydroxy- Pregnarie-ILZO-dione as shown in Preparations 1 and v2.

Another starting compound for the preparation 'of 1 1 04,1711 dihydroxynormalpregnane 3',20-dione and 11a,170c-dihydr'oxyallopregnane-3,ZO-dione is 1'1or,17ot-dihydroxyproges+ "terone [Meister et al., I. Am. Chem. vSoc., 75, 416* (1953)].

Another starting compound for the preparation of 11a,17a-dihydroXypregnane-3,20-dione is 4-chloro- 110;,17a-dihydroxypregnane-3,2O-dione [Levin et. al., I. Am Chem. Soc. 75, 502'-(,1953)]. The corresponding bromo compound, 4-bromo-11a,17a-dihydroxypregnane- 3,20-dione, prepared by simultaneous oxidation and vbromination' of 3e,11a,17a-tribydroxypregnan-ZO-one with N-bromosuccinimide (Preparation 6) can also be used.

Starting materials "for the preparation of the Ila-esters of11a,17a-dihydroxypregnane-3,ZO-dione are obtained by esterifying 30c, la,17a-trihydroxypregnan-ZO-ones and lectively hydrolyzing the thus-obtained 3a,11a-diacylo'xy. 17a-trihydroxypregnan-ZO-ones (of Preparations 3 and 4) or by esterifying 11s,l7a dihydroxyprogesterone or 4- halo-l 1a,17wdihydroxypregnane-3,20'dione. Esterification can be accomplished by standard methods sucha! by admixing lla,17wdihydroxyprogesterone or 4-halo-- 11a, 17a-dihydroxypregnane-3,ZO-dione with an acylating agent such as, forexarnple, ketene, an acid, acid chloride or bromide'or an acid anhydride, or other known acyla't! g agent, usuallygin a solvent, such as", for example,

the boiling point of the reaction mixture, usually about room temperature, for a period between about axhalf hour I and about 96 hours. The time of reaction as well as the temperature at which the reaction is carried out, the

ing into ice or cold water, collecting in an appropriate solvent, and washing with successive portions of a mildly ,1 basic solution and water to obtain a solution of the product which is essentially neutral. In some instances,the ester crystallizes from the reaction mixture, in which case it is advantageously separated by filtration or other means, washed with water, and thereafter purified by conventional means, such as, by recrystallization from a suitable solvent or by chromatographic purification, as deemed necessary.

Representative Ila-esters of 3u,11a,17a-trihydroxypregnan-ZO-one, 11a,17a-dihydroxyprogesterone or 4-chloro- 11a,l7aa-dihydroxypregnane-3,20-dione which can be used as starting materials include the formate, acetate, propionate,)S-cyclopentylpropionate, butyrate, isobutyrate, valerate, isovalerate, hexanoate, heptanoate, octanoate, ben zoate, phenylacetate, mono-chloroacetate, diand trichloroacetate, salicylate, haloand nitro-benzoa-tes, anisate, toluates, gallate, acid succinates, maleates, tartrates, citrates, oxalates, and like hydrocarbon carboxylic acid, and other like acids possessing from one to eight carbon atoms, inclusive.

According to one procedure the novel compound,v 11a, 17u-dihydroxynormalpregnane and esters can be prepared by oxidation of 3a,11a,17a-trihydroxypregnan-20rone; orv esters thereof with tertiary butyl-hypochlorite'; (Examples 1 and 2).

According to another procedure, the novel compounds, 11a,17a-dihydroxynormalpregnane-3,20-dione and 11a,

1'7a-dihydroxyallopregnane-3,ZO-dione, or the correspond- 5 ing lla-esterstthereof, can be prepared 'by hydrogenatyr'icline, or the lik e'jor an inert solvent, including solvents' "'like 'benzene, toluene, ether,- and the like and heating at a temperature between about zero degrees centigrade and of, in the presence of a palladium hydrogenation catalyst (Examples 3 and 4) supported by a catalyst support, such as zinc, oxide-carbonate or charcoal at room temperature, suitablyat about twenty to thirty degrees centigrade.

According to a third procedure, 11a,17a-dihydroxypregnane-3,20-dione can be prepared by reduction of 4-chloro-l1a,17a-dihydroxypregnane-3,ZO-dione with acetic acid andjzinc dust at room temperature as shown in Example 5. Ila-esters of l1a,l7u-dihydroxynormalpregnane-3,20- dione and 110 ,17a-dihydroxyallopregnane-3,2O-dione can be obtained as already stated by oxidizing the correspond ing Ila-esters of 3u,1la,17a-trihydroxypregnan-ZO-one or by hydrogenating the corresponding Ila-esters of 11,

17a-dihydroxyprogesterone or reducing the corresponding Ila-ester of 4-chloroor bromo-l1a,l7a-dihydroxypregnane-3,20-diones. An alternate procedure to obtain llaesters of 11a,17a-dihydroxypregnane-3,ZO-diones is to esterify the obtained products, 11a,l7a-dihydroxynormalpregnane-3,20-dione and its allo isomer, 110:,17oc-dihY- droxyallopregnane-3,20-dione, by conventional procedures, as discussed above in connection with the esterification of the starting materials.

The following examples are illustrative of the products of the present invention and their preparatiombut are not to tbe construed as limiting.

r PREPARATION l 3a,]7a-dihydr0xypregnane-11,20-dione ZO-ethylene glycol v ketal A mixture of 260 milligrams of 3,17a-dihydroxypregnane-ll,20-dione.lKritchevsky, Garmaise, and Gallagher,

I. Am. Chem. 800., 74-, 483 (1952)], five milliliters of ethylene glycol, fifty milligrams of. para-toluenesulfonic acid monohydrate and 100 milliliters of benzene was placed in areaction flask which was equipped with a reflux condenser and a water trap so arranged that the condensed vapors passed through the water trap before returning to the reaction flask. The mixture was heated to reflux and was allowed to reflux for five hours while at the same time being agitated. The water which formed was removed by cordistillation with benzene and was collected in the water trap. The reaction mixture was cooled and poured into a dilute solution of sodium bicarbonate. The benzene layer was separated, washed with water, dried and con entrated to dryness. The residue was chromatographed over forty grams of Florisil magnesium silicate using eight-milliliter portions of a mixture of ethylene dichloride with successively greater proportions of acetone for elution. The material, which was eluted with ethylene dichloride-acetone (12:1 and 8:1), weighed 141 milligrams after removal of the solvents. Recrystallization from benzene-Skellysolve B (Skellysolve is a mixture of hexanes) gave fifty milligrams of 3a,17a-dihydroxypregnane-l1,20-dione ZO-ethylene glycol ketal melting at 144 to 146 degrees centigrade.

Analysis.-Calculated for C H O C, 70.37; H, 9.25. Found: C, 70.65; H, 9.28.

PREPARATION 2 302,11a,I7a-trihydroxypregnan-20-0ne and 3 0a,] 113,17a-trihydroxypregnan-ZO-one To a solution of two grams of lithium aluminum hydride in 200 milliliters of anhydrous ether was added dropwise, with stirring, two grams of 3a,17a-dihydroxy pregnane-11,20-dione ZO-ethylene glycol ketal from Prep then was admixed with a ten-fold excess of dilute hydro chloric acid and the resulting heterogeneous mixture was stirred vigorously for twenty hours at room temperature. The product was isolated by separating the organic and aqueous layers, extracting the aqueous layer with ether, combining the ether extract with the organic layer, washing the organic .solution twice with water, drying the washed solution over anhydrous sodium sulfate, removing the drying agent by filtration, removing the solvents by distillation under reduced pressure, dissolving the resulting residual oil in ethyl. acetate, and adding Skellysolve B to give an opale'scent solution. The crystals obtained (crop A), 540 milligrams, were removed by filtration, and an additional quantity of Skellysolve B was added to the filtrate. ;The crystals obtained from the diluted filtrate (crop B) were s'eparat'edby filtration and weighed 590 milligrams. An additional quantity of crystals identical with those of crop B was obtained from the remaining mother liquor, by distillation of the-sob vents under reduced pressure, redissolving the residual oil in a minimum amount of ethyl acetate, and diluting with Skellysolve B. Crop A was'recrystallized twice from a mixture of ethyl acetate and Skellysolve B and once from a mixture one.

aration 1 in twenty milliliters of anhydrous benzene.

The mixture then was stirred at room temperature for one hour followed by boiling under reflux for an additional hour. With continued stirring the resulting mixture was cooled and treated cautiously with water added dropwise. The resulting solution containing the 30:,11a, 17a-trihydroxypregnan-20-one 20-ethylene glycol ketals of acetone and Skellysolve Bto give 240 milligrams of 3a,11a,17a-trihydroxypregnan-ZO-oneas needles; melting point 184-186 degrees centigrade; [oc] plus 52 degrees in acetone.

' A nalysis.Calculated,for 0 1-1 0450,- 71.9; H, 9.71. Found: C, 72.2; C, 72.3; H, 9.53; H, 9.66. t

4 17a-trihydroxypregnane 20-one," dissolved in two mi1li liters of pyridine, were treated with one milliliter of acetic anhydride at room temperature. After standing for a period of four hours, the solution, was poured onto fifty grams of crushed ice. After the" ice had melted, the mixture was filtered and the thus-obtained precipitate was recrystallized from ethyl acetate and Skellysolve B to yield pure 301,11a-diacetoxy-l7a-hydroxypregnan-2O- PREPARATION 4 3 11,1 7a-dihydroxy-1Im-acetOxypregnan-ZO-One 4 -ch Zora-1 1 m-benzoyloxy-l 7a-hydr0xypregnane- 3,20-d i one One hundred milligrams (100 milligrams) of 4-chloro- 11a,17a-dihydroxypregnane-3,20-dione, dissolved in two milliliters of pyridine, were treated with one milliliter of benzoyl chloride at room temperature. After standing for a period of sixteen hours the solution was poured into ice water and filtered. The precipitate-was recrystallized from a mixture of ether and hexane (Skellysolve B) to yield pure 4-ch1oro-1lwbenzoyloxy-lh-hy droxy-pregnane-3,20-dione.

PREPARATION 6 4-brom0-11u,I 7a-dihydroxypregnane-3,20-di0ne To a solution of milligrams of 3a,11oz,17a-trihydrbxy-pregnan-ZO-one, dissolved in three milliliters of) earnest tertiary butyl alcohol, was added 90 milligrams of: N bromosuccinimide in seven milliliters of tertiary butyl alcohol followed by three milliliters of 0.08 N sulfuric acid. After six hours the excess of hydrobromous acid wasdestroyed by the addition of a few drops of sodium bisulfite solution. The solvent was evaporated and the remaining crystals washed well. with water. Recrystallization from alcohol .gave pure 4-bromo-1la,17u-dihydroxypregnane-3,ZO-dione.

PREPARATION 7 4-bromo-1 1 wace toxy-I 7 a-h ydroxy pregnane-iZO-dioize PREPARATION 8 1 I u-acetoxy-l 7 whydroxyprogesterone To a solution of 11a,l7u-dihydroxyprogesterone in. pyridine about two molar equivalents of acetic anhydride was added. The'mixture was allowed to stand for one hour at room temperature, :then diluted with water, cooled in a refrigerator and filtered- The thus-obtained crystals of 11a-acetoxy--1'7a-hydroxyprogesterone were washed and recrystallized from-ethyl 'acetate-Skellysolve B (hexanes).

In the same manner as shown in Preparations 3, 4, 5, J

7, and 8, other Ila-esters of 3a,l1a,1'7a-trihydroxypreg nan-ZO-one 4-chloroand 4-broinoofl1a,17a-dihydroxypregnane-3,20-dio'ne or of 1la,17a dihydroxyprogesterone are prepared. Such representative Ila-esters of 30;,1'111, I7a-trihydroxypregnan-ZO-one, 4-halo-1la,17a-dihydroxypregnane-3,2'O-dione and 11a,17a-dihydroxyprogesterone include one to eight carbon atoms carboxylic acid acyloxy' esters of saturated or'unsaturated aliphatic, cycloaliphatic, aryl, arylalkyl, alkaryl, mono, di, or polycarboxylic acids having less than eightcarbon atoms, which form ester groups such as, for example, dimethylacetoxy, trimethylacetoxy, propionyloxy, b'utyryloxy, isobutyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, phenylacetoxy, toluyloxy, anisoyloxy, salicyloyloxy, gallyloxy, cyclopentyltormyloxy, ct-cyclopentylpropionyloxy, acrylyloxy, cyclohexylfor'myloxy, the half and di-esters of polybasic acids such as malonic, maleic, succinic, tartaric, citric, glutaric and adipic acids, and the like. The acids may also contain non-interfering substit-, uents, such as mono or poly chloride, bromo, hydroxy, methoxy, mercapto, and the like if desired.

PREPARATION 9 Palladium catalyst supported on zinc carbonate-zinc oxide -mixture Eleven grams of anhydrous zinc chloride was dissolved in 100 milliliters of water at seventy degrees centigrade and a twenty percent aqueous solution of sodium carbonate was added in excess, with constant stirring, forming a precipitate of zinc carbonate. The precipitate was filtered, washed free of alkali with warm water and resuspended in 100 milliliters of water forming a slurry. To the aqueous slurry was added five milliliters of a palladium chloride solution containing 0.5 grams of palladium and then one milliliter of thirty-seven percent aqueous formaldehyde 7 solutions; The resulting red-- brown colored mixture was'avarmed on a steam bath tohyp ochl01'ite. Representative lltz-esters'fthus obtainedxin,

elude: Il propionyloxy 17a hydroxy-pregnane3,20 dione, I'l'ct (,8 cyclopentylpropionyloxy)'- l'7a-hydroxy about sixty; degrees centigrade. and; a :thirty' present aqueous: solution of sodium hydroxide. then added dropwise, with continuous stirring, until the. pH of the mixture reached nine, at which point palladium precipitated. The black-colored precipitate was washed by decantation with ten successive fifty-milliliter portions of water and thenv filtered under suction. The precipitate on, the filter funnel. was washed six times, dried by suction, and heated in an oven at 210 degrees centigrade for a period-of eleven hours. Six and eight-tenthsg'rams of a brown colored. catalyst consisting of palladium: supported. on a zinc carbonate-zinc oxide mixture was obtained.

EXAMPLE 1 I I 1 1 u,] 7 a-dihydroxy pregnane-3,20-dr'0ne To five hundredmilligrams (5 00 milligrams) of 3a, 11 ,17a-trihydroxypregnan-ZO-one (Preparation 2), dissolved in ten milliliters of anhydrous tertiary butyl alcohol was added 0.6 milliliter of tertiary butyl hypochlorite, prepared according to the procedure of Chettaway and Backeberg, J. Chem. Soc., 125, 2999 (1923). The reaction mixture was kept in the dark and stirred for four hours at room temperature (twenty to thirty degrees centigrade) whereafter the whole was evap-' orated to dryness at room temperature (twenty to thirty degrees centigrade) giving 11a,l7a-dihydroxypregnane-3, 20-dione of melting point 187 to 188' degrees centigrade; The infrared spectrum of this compound agreed with the structure postulated for 11a,17a-dihydroxypregnane-3,20- dione.

. .EXAMPLE 2 1'1 u-zzcetoryJ 7 whyttro 'pregrzane-lZO-di one .In the same manner as described in Example 1,1111.- a'cetoxy #304,170; dihyd'roxypregnane 20 one .(Prepara 1 .t'ion 4), dissolved in tertiary "butyl alcohol, was oxidized. swith tertiary butyl hypochloriteat roomtemperature to give llu acetoxy 17a hydroxy -j pregnane -'3,20-dione. In the same manner as 'inExamples 1 and 2, other 1105 acyloxy 17a hydroxypregnane. 3,20 dio'nesfare prepared by oxidizing the corresponding 3a,17a.-dil1ydroxy 11a acyIoXypregnane-ZO-Ones with tertiary butyl pregnane-3,20-dione, I1ubutyroxy-17 -hydroxypregnane- 3,20-dione, 11a isobutyroxy- 17a hydroxypregnane-3,

2O dione, Ila valeryloxy-17a -.hydroxypregnane-3,20

dione, 11cc hexanoyloxy 17a hydroxypregnane 3,20- dione, 11a heptanoyloxy 17a li'ydroxYpregnane-SJO- dione, 11w-octanoyloxy-17ot-hydroxypregnane-3,20 dione, 11cc benzoyloxy l7m-hydroxypregnane-3,ZO-dione, 11aanisoyloxy 17a hydroxypregnane 3,20- dione, llatoluyloxy 17u-hydroxypregnane-3,20-dione, lla-gallylk oxy 17a hydroxypregnane 3,2'0 dione, 11cc hemisuccinyloxy 17oz hydroxypregnane 3,20 dione, 11dhemimaleyloxy 17oz hydroxypregnane 3,20-dione, 11ahemitartaryloxy 17a hydroxypregnane-S,ZO-dione, 11ozdihydrogencitryloxy 17whydroxypregnane 3,20-dioue,

11cc hemioxalyloxy 17oz --hydroxypregnane-S,ZO-dione, 11a -'toluenesulfonyloxy 17a -.hydroxypregnane 3,20- l dione, and the like.

EXAMPLE 3 11a,17a diltydroxynormalpregnane-3,20 dione'tmd 1 I a,] 70: dihydroxyallopregnarte-3,20-dione 3 ,Five hundred milligrams (500 milligrams.) of a mixture of palladium on zinc oxide-zinc carbonate containing 7.5 percent of palladium (Preparation 9) suspended in fifteen milliliters of methanol was hydrogenated at a pressure of twenty pounds per square inch at room temperature, about 25 degrees Centigrade. To this mixture was added a solution of one gram of 11a,17adihydroxyprogesterone dissolved in milliliters of methanol. The hydrogenation was thencontinued-at twenty pounds per Square inch until one mole equivalent of hydrogen hadbeen absorbed. The catalyst was then removed by filtration and the filtrate was chromatographed over a column con taining twenty grams of a mixture consisting of activated carbon (Darco 6-60) and diatomaceous earth (celite) in a one to two ratio. The following 200-milliliter frac tions were collected: 1

Fractions 1 to 15, acetone; fractions 16 to 20, methylene dichloride.

Fractions 1 and 2 (acetone) were combined, evaporated and recrystallized from ethyl acetat'e-Skellysolve B (hexanes) yielding 200 milligrams of 1la,l7a-dihydroxynormalpregnane-3,20-dione of melting .point 186 to 188 degrees ccntigrade and rotation [a] +4 (in chloroform).

Fractions 17 and 18 (methylene dichloride) were combined, evaporated and recrystallized from. ethyl acetate- Skellysolve B' yielding five milligrams of llot,l7u-dlhydroxyallopregnane-3,20-dione of melting point '203 to 206 degrees centigrade. The-infrared spectrum of this compound confirmed the structure of 11a,17a-dihydroxya1lopregnane-3,20-dione.

Paper chromatography on the crude syrup resulting from the hydrogenation indicated a ratio of one part of.

allo to nine parts of the normal product.

EXAMPLE 4 v 1 or acetoxy 12's: hydroxynormalpregnane 3,20-drone and 11a acetoxy 17a-hydr0xyn0rmalpregnane-3,20-

dione In the same manner as given in Example 3, lla-acetoxy 17a-hydroxyprogesterone was hydrogenated in the presence of a palladium catalyst supported on charcoal to nane 3,20 dione, 11 octanoyloxy'17a-hydroxynonnal pregnane-3,20-dione and 11a-octanoyloxy-17u-hydroxyaIlopregnane-3,20-dione,' 11a-phenylacetoxy-17a-hydroxynormalpregna'ne-3,20-dione and "1 lu-phenylacetoxy-lhhyd'roxyallopregnane-3,20-dione, 11a-monochloroacetoxyl7m-hydroxynormalpregnane-3,20-dione and 1 lot-monochloroacetoxy 17ot-hydroxyallopregnane-3,ZO-dione 11adichloroacetoxy 17a hydroxynormalpregnane 3,20 dione and 1la-dichloroacetoxy-17a-hydroxyallopregnane- 3,20 dione, 11a trichloroacetoxy l7u-hydroxynormalpregnane 3,20 dione and 1la-trichloroacetoxy-17a-hy* dro'xyallopregnane-3,20-dione, llu-salicyloyloxy-lh-hydroxynormalpregnane-I:,ZO-dione and lla-salicyloyloxyl7a-hydroxyallopregnane-3,20-dione, lla-chlorobcnzoyloxy 17oz hydroxynormalpregnane 3,20-dione and 11achlorobenzoyloxy 170'. hydroxyallopregnane 3,20

yield 11a-acetoxy-lf7a-hydroxypregnane-3,ZO-dione and 11m acetox'y l7pc-hydroxyallopregnane-3,20-diones which were separated by chromatography over a column of activated carbon and' diatomaceous earth with acetone and methylene dichloride.

' EXAMPLE 5 11a benzoy'lox 17a hydroxypregna'ne-iZO-dione and 11 u-benzoyloxy-I 7ahydro.xyallopregnane-3,20-di0ne In the same manner as given in Example 3, Ila-b811- zoyloxy17u-hydroxyprogesterone was hydrogenated in the presence'of a palladium catalyst on zinc oxide-carbonate to yield 11a-benzoyloxy-17a-dihydroxypregnane- 3,20 dime and lla-benzoyloxy-17a-dihydroxyallopregnane-3,20-diones which were separated by chromatography as shown in Examples 3 and 4.

In the same manner as in Examples 3, 4, and 5, other Ila-esters of 11m,17a-dihydroxynormalpregnane-3,20di-. one and '11a,17a-dihydroxyallopregnane-3,20-diones are prepared byehydrogenating the corresponding 11a-acyl oxy-l7a-hydroxyprogesterone with hydrogen in the pres- 3,20 dione and 11wheptanoyloxy-l7a-hydroxyallopreg dione, 1 1m-nitrobenzoyloxy-l7a-hydroxynormalpregnane:

3,20-dione and 11d-nitrobenzoyloxy-17r-hydroxyallopregnane-3,20-dione, l1a-anisoyloxy-l7a-hydroxynormalpregnane-3,20-dioneand 11u-anisoyloxy-17a-hydroxyallopreg nane 3,20-dione, '11a-toluyloxy-l7a-hydroxynormalpregname-3,20-dione. and 1lwtoluyloxy-17a-hydroxya1lopregmane-3,20-dione, 11a 9 gallyloxy-17a-hydroxynormalpregnane-3,20.-dione and 11a-gallyloxy-17a-hydroxyallopregname-3,20-dione, lla-hemisuccinyloxy-fla hydroxynormalpregnane-3,20-dione and l1a-hemisuccinyloxy-17a-hy- .drox'yallopregnanc 3,20-dione, 1la-hemimaleyloxy-17ahydroxynormalpregnane-3,20 dione and lla-hernimaleyloxy 170: hydroxyallopregnane-3,20-dione, lla-hemitartaryloxy' 17a hydroxynormalpregnane. 3,20 dione I and 11a hemitar'taryloxy-l7a-hydroxyallopregnaner3,20

dione, 1 1a dihy drogencitryloxyl'7a hydroxynormalpre'gnane 3,20 dione and 11 5- dihydrog'encitryloxy l7u-hydroxyallopre'gnane 3,20 dione, 1 1a-hemioxalyloxy-17 ochydroxynormalpregnane-3,ZO-dione and ,.l1o -hemioxalyl oxy-17ahydroxyallopregnane-3 ,ZO-dione, lla-toluenesulfonyloxy 17a hydroxynormalpregnane 3,20-dione and 11m toluenesulfonyloxy 17a hydroxyallopregnane 3,20-dione, and the like.

Ila-esters of 1la,17a-dihydroxynormalpregnane-3,20-

diode and 11a,l7a-dihydroxyallopregnane-3,20-dione can also be obtained by esterification of lla-17a-dihydroxynormalpregnane-3,20 -dione and 11a,'17a-dihydroxyallopregnane-ZJO-dione (obtained in Example 1) by the methods already described. i

I EXAMPLE 6 v 11a,17a dihydroxynormalpregnane-3,20-di0ne To a solution of 4-chloro-11a,17u-dihydroxypregnane- 3,20-dione [-Levin et al., J. Am. Chem. Soc.', 75, 502 (1953)] in acetic acid was added finely powdered zinc dust.-- The mixture was stirred at 22 to 25 degrees centigrade (room temperature) for a period of three hours, then filtered through glass wool, the filtrate was diluted with water and neutralized by the addition of sodium hydroxide solution. After cooling of the solution :,1704- dihydroxynorinalpregnane-3,20-dione precipitated and was collected on a filter, washed and repeatedly recrystallized from ethyl acetate and Skellysolve B (hexanes) to give the pure material of melting point 191 to 192.5 degrees centigrade.

EXAMPLE 7 7 J 1 m-benzoyloxy-l 7u-hydroxypregnwne-3,20-di0ne In the same manner as given in Example 6, Ila-hen zoyloxy-17a-l1ydroxypregnane-3,20-dione is obtained by treating a solution of 4-chloro-1la-benzoyloxy-flwhydroxypregnaneQQ-dione (Preparation 5) in acetic acid with zinc. I

Similarly other Ila-esters of 1la,17a-dihydroxypregname-3,20-diones are obtained by treating'the corresponding 4 chloro-l1m-acyloxy-17a-hydroxypregnane-3,20-diones with zinc dust imaceticacid. 1

9 EXAMPLE 8 IIa-acemxy-I h-hydroxypregnane-iZO-dione In the same manner as given in Examples 6 and 7, 11- acetoxy- 17-hydroxypregnane-3,20-dione is obtained by treating 4-bromo-1la-acetoxy-17a-hydroxypregnane-3,20- dione (Preparation 7) dissolved in acetic acid, with zinc dust.

Treatment of other 4-bromo-11ct-acy1oxy-17a-hydroxypregnane-3J0-diones, wherein the acyloxy group is, for example, propionyloxy, butyroxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, salicyloyloxy, fi-cyclopentylpropionyloxy, and the like, with zinc dust and acetic acid is productive of the corresponding 1 1a-acyloxy-17a-hydroxypregnane-3,20diones.

It is to be understood that this invention is not to be limited to the exact details of operation or exact com- 10 pounds shown and described as obvious modifications and equivalents will be apparent to one skilled in the art and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. 11a,17a-dihydroxynormalpregnane-3,20-dione.

2. 11oz acyloxy 17a hydroxynormalpregnane 3,20-dione wherein the acyl radical is of a hydrocarbon carboxylic acid containing up to and including eight carbon atoms.

3. 11a acetoxy 170: hydroxynormalpregnane 3,20-dione.

4. 11a benzoyloxy 17 hydroxynormalpreguane 3,20'dione.

No references cited. 

1. 11A,17A-DIHYDROXYNORMALPREGNAME-3,20-DIONE.
 2. 11A - ACYLOXY - 17A - HYDROXYNORMALPREGNANE 3,20-DIONE WHEREIN THE ACYL RADICAL IS OF A HYDROCARBON CARBOXYLIC ACID CONTAINING UP TO AND INCLUDING EIGHT CARBON ATOMS. 